Water‐Soluble Prodrug of Antimicrotubule Agent Plinabulin: Effective Strategy with Click Chemistry

Yakushiji, Fumika; Tanaka, Hironari; Muguruma, Kyohei; Iwahashi, Takahiro; Yamazaki, Yoshihiro; Hayashi, Yoshio

doi:10.1002/chem.201102293

Cited by 16 publications

(18 citation statements)

References 74 publications

(61 reference statements)

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“…56 exhibited an IC 50 value that was one-tenth the value of 7 under normal conditions. 62,63) The reduced IC 50 value was attributed to the direct reaction of the monolactim prodrug 56 with small amounts of esterases produced by the cells or with the inner components of the cells.…”

Section: Evaluation Of Cytotoxicitymentioning

confidence: 89%

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Medicinal Chemistry and Chemical Biology of Diketopiperazine-Type Antimicrotubule and Vascular-Disrupting Agents

2013

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Section: Evaluation Of Cytotoxicitymentioning

confidence: 89%

“…Therefore, we attempted to develop a water-soluble prodrug of 7 to avoid the safety or quality of life risks to patients. 50,51) …”

Section: Development Of a Water-soluble Prodrug Of Plinabulinmentioning

confidence: 99%

Medicinal Chemistry and Chemical Biology of Diketopiperazine-Type Antimicrotubule and Vascular-Disrupting Agents

2013

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“…23,24 Prodrug 2 exhibits a sufficiently high water solubility (6.4 mg/mL) and can be used as an intravenous agent. Ester cleavage of prodrug 2 by esterase yields the parent compound 1 23 .…”

Section: Introductionmentioning

confidence: 99%

Novel Hybrid Compound of a Plinabulin Prodrug with an IgG Binding Peptide for Generating a Tumor Selective Noncovalent-Type Antibody–Drug Conjugate

Muguruma¹,

Yakushiji²,

Kawamata³

et al. 2016

Bioconjugate Chem.

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Although several approaches for making antibody-drug conjugates (ADC) have been developed, it has yet to be reported that an antibody binding peptide such as Z33 from protein A is utilized as the pivotal unit to generate the noncovalent-type ADC (NC-ADC). Herein we aim to establish a novel probe for NC-ADC by synthesizing the Z33-conjugated antitumor agent, plinabulin. Due to the different solubility of two components, including hydrophobic plinabulin and hydrophilic Z33, an innovative method with a solid-supported disulfide coupling reagent is required for the synthesis of the target compounds with prominent efficiency (29% isolated yield). We demonstrate that the synthesized hybrid exhibits a binding affinity against the anti-HER2 antibody (Herceptin) and the anti-CD71 antibody (6E1) (Kd = 46.6 ± 0.5 nM and 4.5 ± 0.56 μM, respectively) in the surface plasmon resonance (SPR) assay. In the cell-based assays, the hybrid provides a significant cytotoxicity in the presence of Herceptin against HER2 overexpressing SKBR-3 cells, but not against HER2 low-expressing MCF-7 cells. Further, it is noteworthy that the hybrid in combination with Herceptin induces cytotoxicity against Herceptin-resistant SKBR-3 (SKBR-3HR) cells. Similar results are obtained with the 6E1 antibody, suggesting that the synthesized hybrid can be widely applicable for NC-ADC using the antibody of interest. In summary, a series of evidence presented here strongly indicate that NC-ADCs have high potential for the next generation of antitumor agents.

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“…Furthermore, the water-solubilizing triazole auxiliary, which was cleaved from the mother skeleton via an esterase hydrolysis reaction, was shown to be cellularly non-toxic. 11) These results suggested that it was worthwhile to pursue further optimization of this prodrug system.…”

mentioning

confidence: 99%

“…4) Therefore, a variety of water-soluble paclitaxel prodrugs have been developed to improve the patient's burden. [5][6][7][8][9] Previously, we reported the design and synthesis of a water-soluble prodrug of plinabulin (1) 10) as a monolactim serine-type derivative 2 11) using click chemistry [12][13][14] (Fig. 1).…”

mentioning

confidence: 99%

Prodrug Study of Plinabulin Using a Click Strategy Focused on the Effects of a Replaceable Water-Solubilizing Moiety

Yakushiji

Tanaka

Muguruma

et al. 2012

CHEMICAL & PHARMACEUTICAL BULLETIN

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Plinabulin (1) is a potent anti-microtubule agent, however, its low water solubility has to be improved for the advantage in pharmacokinetics and chemotherapy. In this report, the replaceable water-solubilizing moiety of the water-soluble prodrug of plinabulin (1) was investigated. The properties of the water-soluble prodrugs of plinabulin (1), in which the water-solubilizing part was replaced with a new functionality, were evaluated. The newly introduced water-solubilizing moiety provided interesting effects on the water solubility and half-life of the prodrugs.Key words water-soluble prodrug; anti-microtubule agent; click chemistry; plinabulin; monolactim 'Prodrug' research is one of the most important fields of medicinal chemistry. In particular, improvements in water solubility have been studied extensively.1) Paclitaxel, for example, exhibited potent anti-microtubule activity 2) as intravenous (i.v.) injection. Due to its low water solubility (0.25 µg/mL), 3) it was initially formulated with the detergent cremophor EL, which induced hypersensitivity. 4) Therefore, a variety of water-soluble paclitaxel prodrugs have been developed to improve the patient's burden. 5-9)Previously, we reported the design and synthesis of a water-soluble prodrug of plinabulin (1) 10) as a monolactim serine-type derivative 2 11) using click chemistry 12-14) (Fig. 1). Plinabulin (NPI-2358) (1) (cytotoxic activity: IC 50 =15 nM in HT-29 cells) is a derivative of S-(−)-phenylahistin 15,16) and phase II clinical trials have been undertaken worldwide [17][18][19] by way of i.v. injection as a promising vascular disrupting agent (VDA). [20][21][22][23][24] Plinabulin (1) showed low water solubility (<0.1 µg/mL), which forced the co-injection of a solubilizing agent, such as paclitaxel. To improve the pharmacokinetics and chemotherapeutic index, the water-soluble prodrug 2 was developed. The water solubility of α-amino acid type derivative 2 was determined to be 6.38 mg/mL, and the in vitro halflife (t 1/2 ) in the presence of porcine liver esterase was found to be 59.9 min. These values make the compound appropriate for i.v. injection without inclusion of a solubilizing agent. Furthermore, the water-solubilizing triazole auxiliary, which was cleaved from the mother skeleton via an esterase hydrolysis reaction, was shown to be cellularly non-toxic.11) These results suggested that it was worthwhile to pursue further optimization of this prodrug system.In this paper, we investigated the replaceable water-solubilizing moiety to evaluate its influence on prodrug water solubility and half-life. As a water-solubilizing moiety, we focused on two types of polar groups. One was L-carnitine (3), 25) which is an γ-amino acid derivative involved in lipid metabolism in the human body. The unprotected polar functional group of the azide 4 26) is a β-hydroxycarboxylic acid moiety, that is similar to the serine-type structure used in prodrug 2, with a higher number of carbon atoms. These slight changes were expected to provide interesting effects on th...

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Water‐Soluble Prodrug of Antimicrotubule Agent Plinabulin: Effective Strategy with Click Chemistry

Cited by 16 publications

References 74 publications

Medicinal Chemistry and Chemical Biology of Diketopiperazine-Type Antimicrotubule and Vascular-Disrupting Agents

Medicinal Chemistry and Chemical Biology of Diketopiperazine-Type Antimicrotubule and Vascular-Disrupting Agents

Novel Hybrid Compound of a Plinabulin Prodrug with an IgG Binding Peptide for Generating a Tumor Selective Noncovalent-Type Antibody–Drug Conjugate

Prodrug Study of Plinabulin Using a Click Strategy Focused on the Effects of a Replaceable Water-Solubilizing Moiety

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